OSTEOPOROSIS -Medical Management of Men and Women who have (or are at risk of ) Osteoporosis

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1 Basingstoke, Southampton and Winchester District Prescribing Committee OSTEOPOROSIS -Medical Management of Men and Women who have (or are at risk of ) Osteoporosis Frail, increased fall risk + housebound Advise calcium gram and colecalciferol 20 micrograms (800 units) daily Assess falls risk. Advise or refer to Falls Service as appropriate No High falls risk Current or frequent past use of glucocorticoids No Previous fragility fracture (including vertebral fractures) No Is it appropriate to use Frax assessment tool? (see page 4 of guidelines) Yes Assess fracture risk using Frax tool then use the link to NOGG guidance Measure BMD if recommended and recalculate fracture risk Reassure, General measures 3, Reassess in < 5 yrs depending on clinical context Risk Factors Advise treatment Yes Yes Age 75yrs Refer to separate guidance on page 2 of guidelines Investigations 1 Age 75yrs Measure BMD (DXA scan, hip + spine) Normal T score Above -1 Reassure General Measures 3 Osteopenia T score -1 to -2.5 Investigations 1 General Measures 3 Consider treatment if T score below with fracture ( esp. vert. fracture) Osteoporosis 2 T score below 2.5 Investigations 1 Advise Treatment ALENDRONATE 70mg WEEKLY (1st Line) Advise three/six monthly review of adherence to therapy as non-compliance is common. Seek specialist opinion if patient sustains a fracture after 1 year on compliant therapy. 1 Investigations FBC, ESR (If ESR raised, measure serum paraproteins and urine Bence Jones protein) Bone and liver function tests (Ca, P, Alk phos, albumin, ALT) Renal function Serum 25 0H Vit D Consider PTH if: Calcium level raised Calcium level in upper quartile of normal range and vitamin D deficient Additional tests if indicated: Serum TSH Coeliac screen (TTG) Serum testosterone, LH and SHBG, PSA (men) Consider GT Lateral thoracic and lumbar spine X rays BMD if monitoring required Isotope bone scan 3 General measures Recommend good nutrition esp. with adequate calcium and vitamin D (see link to dietary calcium calculator) 16 Recommend regular weight bearing exercise Maintain ideal body weight Avoid tobacco use and alcohol abuse ( > government recommendations) Assess falls risk and give advice if appropriate Consider any of the following 2 nd line treatments if alendronate not suitable because patient unable to comply with the special instructions for the administration of alendronate has a contraindication to, is intolerant of, or has a lack of clinical response to alendronate ALTERNATIVE BISPHOSPHONATE Refer to Page 5 and Table A on Page 8 of guidelines Specialist Initiated DENOSUMAB 60mg s.c. injection 6 monthly Amber Drug (Check current status) see Shared Care Guidelines* Refer to page 6 of guidelines STRONTIUM 2 g at night Refer to page 7 of guidelines Teriparatide ( refer to page 7of guidelines) Intravenous bisphosphonates Denosumab (Check if current status amber/green) RALOXIFENE 60mg daily Refer to page 7 of guidelines All patients must be prescribed Calcium gram + colecalciferol 20 micrograms (800 units) daily unless clinician is confident dietary calcium intake is adequate and patient is vitamin D replete. (see link to dietary calcium calculator) 16. Prescribe vitamin D 800 units daily alone in patients with adequate calcium intake who only need vitamin D supplement. 2 Consider treatment depending on age General and fracture Measures probability. 3 * Denosumab Shared Care Guideline accessed at: on Pages4PrimaryCare website, Prescribing Folder in GP & Pharmacist sections. Page 1 of 10 pages

2 Basingstoke, Southampton and Winchester District Prescribing Committee ALGORITHM FOR THE MEDICAL MANAGEMENT OF GLUCOCORTICOID-INDUCED OSTEOPOROSIS IN ADULTS Glucocorticoid therapy expected to be 3months or Cumulative dose equivalent to 1.5gram prednisolone per year for patients prescribed repeated short courses Age 65yrs Age 65yrs No previous fragility fracture Previous fragility fracture or incident fracture Investigations 1 Measure BMD (DXA scan, hip + spine Treatment T score above 0 T score between 0 and T score 1.5 or lower 2 RISEDRONATE 35mg WEEKLY (or other bisphosphonate if not tolerated) Reassure General measures 3 General measures 3 All patients must also be prescribed: Calcium gram + colecalciferol 20 micrograms (800 units) daily unless clinician is confident dietary calcium intake is adequate and patient is vitamin D replete. ( see link to dietary calcium calculator) 16. Prescribe vitamin D 800 units daily alone in patients with adequate calcium intake who only need vitamin D supplement. Repeat BMD not indicated unless a daily dose of 10mg or more is required Repeat BMD in 1 3 yr if glucocorticoids continued Initiate osteoporosis management when glucocorticoid is started and stop treatment six months after glucocorticoids stop. Advise three/six monthly review of adherence to therapy. 1 All Patients FBC, ESR (If ESR raised, measure serum paraproteins and urine Bence Jones protein) Bone and liver function tests (Ca, P, Alk phos, albumin, ALT) Renal function Serum 25 0H Vit D Consider PTH if: Calcium level raised Calcium level in upper quartile of normal range and vitamin D deficient Additional tests if indicated: Serum TSH Coeliac screen (TTG) Serum testosterone, LH and SHBG, PSA (men) Consider GT Lateral thoracic and lumbar spine X rays BMD if monitoring required Isotope bone scan 2 Consider treatment depending on age and fracture probability 3 General measures Reduce dose of glucocorticoid when possible, Consider glucocorticoid sparing therapy if appropriate or consider alternative route of administration Recommend good nutrition esp. with adequate calcium and vit D (see link to dietary calcium calculator) 16 Recommend regular weight bearing exercise Maintain ideal body weight Avoid tobacco use and alcohol abuse (> government recommendations) Assess falls risk and give advice if appropriate 2 of 10 pages

3 Basingstoke, Southampton and Winchester District Prescribing Committee CLINICAL RISK FACTORS FOR OSTEOPOROSIS Previous fragility fracture Predisposing medical Current glucocorticoid use 3 months and frequent past use conditions Parental history of hip fracture hyperthyroidism Radiographic osteopenia rheumatoid arthritis Height Loss cm type 1 diabetes Female hypogonadism post-menopause untreated premature menopause drug or surgically induced menopause inflammatory bowel disease malabsorption/coeliac disease premenopausal amenorrhoea 6 months, (excl pregnancy) prolonged immobility Body Mass Index (<19kg/m 2 ) organ transplantation Caucasian/Asian origin hyperparathyroidism Current smoking chronic liver disease 3 units alcohol daily Male hypogonadism ** Drugs associated with osteoporosis excessive levothyroxine replacement therapy long-term heparin anticonvulsants antipsychotics Lithium Depo-Provera, 2yrs treatment Aromatase inhibitors*, GnRH analogues** (separate guidance) Proton Pump Inhibitors*** (separate guidance) * Aromatase inhibitor guidance available as algorithms in Appendix 1 to this guideline 1. ** Androgen Deprivation Therapy The use of GnRH analogues in men is associated with bone loss and fractures but there is no official guideline to date on its management. Recommend BMD at initiation of therapy (when any additional secondary causes of bone loss are ruled out) and consider bisphosphonate or denosumab therapy for men with osteoporosis and fragility fractures, or men with a T score -2.5 SD or lower. Also consider treatment for men with a T score between -1.0 and -2.5 SD on GnRH analogues if additional risk factors were present. All should have a follow-up BMD in 1 2 years 2. All patients must also be prescribed Calcium gram + colecalciferol 20 micrograms (800 units) daily unless clinician is confident dietary calcium intake is adequate and patient is vitamin D replete. (see link to dietary calcium calculator) 16 Prescribe vitamin D 800 units daily alone in patients with adequate calcium intake who only need vitamin D supplement. *** Proton Pump Inhibitors 3 - can increase the risk of fractures, particularly when used at high doses for over a year in the elderly. Patients at risk of osteoporosis should maintain an adequate intake of calcium and vitamin D (see link to dietary calcium calculator) 16 and if necessary, receive other preventative therapy (see treatment algorithm on page 1 of these guidelines). 3 of 10 pages

4 Assessment of Fracture Risk using Frax The FRAX tool is an algorithm which calculates a 10 year fracture risk for people aged between 40 and 90 years either with or without BMD values. (Available at and it links to guidance (see below) published by the National Osteoporosis Guideline Group (NOGG) 5 for the management of osteoporosis. See also NICE Clinical Guideline 146 Osteoporosis: assessing the risk of fragility fracture 4 ). 10 year probability of major osteoporotic fracture (%) (Measurement of Bone Mineral Density helps to inform whether treatment is recommended) Assessment without BMD Assessment with BMD Consider using the FRAX tool : In women aged 65 years and over and men aged 75 years and over In women aged under 65 years and men aged under 75 years in the presence of risk factors (see list on page 3 of guidelines) Situations when FRAX may not be appropriate: Do not routinely assess fracture risk in people < 50 yrs unless they have major risk factors (e.g. glucocorticoid use, untreated menopause or previous fragility fracture) Use caution when interpreting the fracture risk in people > 80yrs as predicted 10yr fracture risk may underestimate their short term fracture risk, and when using FRAX for people > 90yrs (the upper age limit for the tool) consider them to be at high risk. The FRAX tool may not adequately weight certain risk factors and therefore may underestimate fracture risk in the following circumstances: Aged > 80yrs Multiple fractures Previous vertebral fractures High alcohol intake Glucocorticoid use (> 7.5mg prednisolone or equivalent per day 3months) Other causes of secondary osteoporosis (including drugs associated with osteoporosis) Frailty Fallers Review FRAX assessment when clinically indicated e.g. change in risk factor status. 4 of 10 pages

5 Therapeutic Agents Available For The Management Of Osteoporosis (See Table A (on page 8) for anti-fracture efficacy of therapies available) Refer to the latest data sheet for full prescribing details about use in elderly, renal and hepatic impairment, contraindications, precautions etc. Refer to the BNF- Guidance on prescribing in renal impairment- for advice on using egfr / calculated creatinine clearance to adjust doses for patients with renal impairment. CALCIUM AND VITAMIN D 3 Adequate levels of calcium and vitamin D 3 (colecalciferol) are required to ensure optimum effects of all the treatments for osteoporosis (see link to dietary calcium calculator) 16. Unless the clinician is confident that the patient has adequate calcium intake and is vitamin D replete, calcium and colecalciferol supplementation at a dose of Calcium gram (equivalent to g Calcium Carbonate) and colecalciferol 20 micrograms (800 units) daily should be prescribed. Prescribe vitamin D 800 units daily alone in patients with adequate calcium intake who only need vitamin D supplement. Avoid colecalciferol in severe renal impairment as it cannot be converted to its active form in the renally impaired. BISPHOSPHONATES Alendronate is the first choice bisphosphonate for the majority of patients Risedronate (now generic) may be prescribed, in patients intolerant of alendronate, in young adults and in patients with glucocorticoid-induced osteoporosis where it may be beneficial due to rapid on/off effect For other bisphosphonates choices see Table A (on page 8 of the guidelines) for site specific anti-fracture efficacy Intravenous bisphosphonates may be used under specialist guidance Oral bisphosphonates should be swallowed whole with a glass of water minutes before the first food or drink (other than water) of the day. Patients should stand or sit upright (not lie down) for at least 30 minutes post dose. Discontinue treatment if oesophageal ulceration, erosion, stricture, or severe lower gastrointestinal symptoms occur. Bisphosphonates should be avoided in patients with moderate to severe renal impairment. ( egfr < 35ml/min/1.73m 2 for alendronate, < 30ml/min/1.73m 2 for risedronate). Atypical femoral fractures (often bilateral) have been reported rarely with bisphosphonate therapy, mainly in patients receiving long-term treatment for osteoporosis. Patients should be advised to report any thigh, hip or groin pain. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered while they are evaluated, and should be based on an assessment of the benefits and risks of treatment. For general advice on duration of therapy see separate section Duration of Treatment on page 8 of the guidelines. Osteonecrosis of the jaw has been reported rarely with IV bisphosphonate use and very rarely with oral use. Adequate oral hygiene should be maintained during and after bisphosphonate treatment. In patients with concomitant risk factors e.g. cancer, chemotherapy treatment, glucocorticoid treatment, or poor oral hygiene, remedial dental work should ideally be completed before starting bisphosphonates. 5 of 10 pages

6 DENOSUMAB (Specialist Initiated AMBER drug currently please check as Amber/Green status may change in near future) Usually initiated in secondary care but may be initiated by GPs, in line with current DPC approved local guidance, if GP confident to do so. (Consult Shared Care Guidelines at on Pages4PrimaryCare website, Prescribing Folder in GP & Pharmacist sections). For the secondary prevention of osteoporotic fragility fractures in postmenopausal women at increased risk of fractures, when bisphosphonates inappropriate. (N.B. UK license for men with osteoporosis awaited) For the primary prevention of osteoporotic fragility fractures in postmenopausal women at increased risk of fracture, when bisphosphonates inappropriate AND patient has combination of very low BMD and independent risk factors. (see reference 15) Hypocalcaemia is a contraindication to Denosumab therapy. Check serum calcium and correct pre-existing hypocalcaemia before initiating Denosumab. A few cases of severe symptomatic hypocalcaemia have been reported in patients at increased risk of hypocalcaemia e.g. with severe renal impairment (creatinine clearance < 30ml/min; egfr 15 29ml/min/1.73m 2 ) or on dialysis. (N.B. The data that hypocalcaemia usually occurs in the first 6 months of therapy but can occur at any time so far relate only to oncology patients prescribed the higher 120mg dose monthly.) Periodic monitoring of calcium levels, at the discretion of the prescriber, is advised in patients at high risk of hypocalcaemia (most commonly those with severe renal impairment and on dialysis). Ensure adequate intake of calcium and vitamin D (see link to dietary calcium calculator) 16 in all patients receiving denosumab (unless hypercalcaemic) 6. Administered as a 60mg subcutaneous injection (at any time of day) at 6 month intervals No dose adjustment required in patients with renal impairment. The SPC states that osteonecrosis of the jaw has been reported (rarely) in patients receiving denosumab with most cases occurring in cancer patients (and very rarely in patients with osteoporosis). Atypical femoral fractures have been reported rarely during long-term ( 2.5 years) treatment 7. Any patient presenting with new or unusual thigh, hip or groin pain should be evaluated for an incomplete femoral fracture. Discontinuation of denosumab therapy should be considered if an atypical femur fracture is suspected, while the patient is evaluated. N.B. To decrease the possibility of duplication of bone protection prescribing it is essential that: a) secondary care inform the patient s GP of the date denosumab therapy was initiated and b) primary care are advised that these details are included in the patient s repeat medication records and entered onto practice recall system for recall at 6 month intervals. (As per shared care guideline see website above) 6 of 10 pages

7 STRONTIUM RANELATE Restricted to the treatment of severe osteoporosis (defined as T score at least -2.5, plus fragility fracture) In postmenopausal women at high risk of fracture In men at increased risk of fracture when bisphosphonates are contra-indicated or cannot be tolerated, or the patient has difficulty complying with their strict ingestion regimen. A recent review of available safety data has raised some concerns about cardiovascular risks 8 : Risk of (non fatal) myocardial infarct is increased and strontium should not be used in patients with a current or past history of ischaemic heart disease, peripheral arterial disease, cerebrovascular disease or uncontrolled hypertension. Assess individual patient s risk before and during treatment. Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking) should only be treated after careful consideration. Risk of thrombo-embolism is increased and strontium is now contraindicated in patients with: current or previous venous thromboembolic events including deep vein thrombosis and pulmonary embolism temporary or permanent immobilisation due to e.g. post-surgical recovery or prolonged bed rest Avoid in severe renal impairment ( egfr 30ml/min/1.73m 2 ). Strontium should be taken at bedtime at least 2 hours after food and/or milk. Severe allergic reactions including DRESS (drug rash with eosinophilia systemic symptoms) have been reported in patients taking strontium. If a rash develops, treatment must be stopped permanently, and the DRESS symptoms treated appropriately. RALOXIFENE Selective oestrogen receptor modulator (SERM) For postmenopausal women with vertebral osteoporosis, with an unsatisfactory response to or an intolerance of bisphosphonates. Avoid in severe renal impairment. TERIPARATIDE (Specialist Use only) Indications restricted to patients with an unsatisfactory response/intolerance to the above therapies AND aged > 65 yrs old who have a T score of 4 SD or below OR aged > 65 yrs old who have a T score of -3.5 SD or below plus at least 2 fractures OR aged yrs old who have a T score of -4 SD or below plus at least 2 fractures Use with caution in moderate renal impairment. Contraindicated in severe renal impairment. HORMONE REPLACEMENT THERAPY recommended as treatment for the prevention of osteoporosis in women with a premature menopause (up to 50 years of age). COMBINATION THERAPY (not including combinations with Calcium and colecalciferol) is not routinely prescribed but may be rarely used under specialist recommendation 7 of 10 pages

8 DURATION OF TREATMENT Oral bisphosphonates, strontium ranelate and raloxifene are recommended for up to five years of treatment. Re-evaluation of the patient may then include DXA scan or evaluation of biochemical markers of bone turnover. After five years of treatment, for patients not considered at high risk of fracture, a drug holiday period of up to three years without therapy can be considered. (N.B Ensure patient is calcium and vitamin D replete [see link to dietary calcium calculator] 16, or continue adequate supplementation). For patients still at high risk of fracture, it appears safe to continue for a further five years of treatment. Teriparatide should be used for up to 18 months, denosumab for up to 3 years in the first instance, and intravenous Zoledronate for up to 3 yrs. TABLE A 5 Effect of major pharmacological interventions on fracture risk when given with calcium and vitamin D in postmenopausal women with osteoporosis Intervention Vertebral Non-vertebral Hip Alendronate A A A Risedronate A A A Zoledronate A A A Denosumab A A A Strontium ranelate A A A Teriparatide (PTH 1-34) A A nae Ibandronate a A A nae Raloxifene A nae nae PTH (1-84) A nae nae in subsets of patients only (post-hoc analysis) a Injection only available on Formulary nae : not adequately evaluated PTH : recombinant human parathyroid hormone Table A 5 Grading of recommendations and evidence levels Levels of evidence for studies of intervention are defined as follows: Ia from meta-analysis of randomised controlled trials (RCTs) Ib from at least one RCT IIa from at least one well designed controlled study without randomisation IIb from at least one other type of well designed quasi-experimental study III from well designed non-experimental descriptive studies, eg comparative studies, correlation studies, casecontrol studies IV from expert committee reports or opinions and/or clinical experience of authorities The validity of candidate risk factors is also assessed by an evidence-based approach: Ia Systematic reviews or meta-analysis of level I studies with a high degree of homogeneity Ib Systematic reviews or meta-analysis with moderate or poor homogeneity Ic Level I studies (with appropriate populations and internal controls) IIa Systematic reviews or meta-analysis of level II studies IIb Level II studies (inappropriate population or lacking an internal control) IIIa Systematic reviews or meta-analysis of level III studies IIIb Case-control studies IV Evidence from expert committees without explicit critical scientific analysis or that based on physiology, basic research or first principles. The quality of the guideline recommendations is similarly graded to indicate the levels of evidence on which they are based: grade A evidence levels Ia and Ib grade B evidence levels IIa, IIb and III grade C evidence level IV 8 of 10 pages

9 References 1. Reid DM, Doughty J, Eastell R et al. Guidance for the management of breast cancer treatmentinduced bone loss: a consensus position statement from a UK Expert Group Cancer Treat Rev 2008; 34: S1 S18. (Full guidance and 2 treatment algorithms available at and the algorithms are also contained in Appendix 1 of this document. 2. Greenspan S. Approach to the Prostate Cancer Patient with Bone Disease. J Clin Endocrinol Metab. Jan 2008, 93(1): MHRA Drug Safety Update April 2012, vol 5 issue 9: A2. 4. NICE Clinical Guideline CG 146 Osteoporosis: assessing the risk of fragility fracture. Aug Guideline for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. Produced by J Compston, A Cooper, C Cooper, R Francis, JA Kanis, D Marsh, EV McCloskey, DM Reid, P Selby and M Wilkins, on behalf of the National Osteoporosis Guideline Group (NOGG). October 2008 and updated July 2010 ( ) 6. MHRA Drug Safety Update October 2012, vol 6, issue 3: A3 7. MHRA Drug Safety Update February 2013 vol 6 issue 7: A1 8. MHRA Drug Safety Update April 2013 vol 6, issue 9 9. Bone and Tooth Society of Great Britain, National Osteoporosis Society, Royal College of Physicians Glucocorticoid induced Osteoporosis: Guidelines for Prevention and Treatment London: RCP, Bone and Tooth Society of Great Britain, National Osteoporosis Society, Royal College of Physicians Clinical Guidelines for the prevention and treatment of Osteoporosis London RCP Update Reginster JY, Seeman E, De Vernejoul MC et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab.2005 May; 90(5): Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med Jan 29; 350(5): NICE Technology Appraisal TA161 Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. October NICE Technology Appraisal TA160- Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in post menopausal women. October NICE Technology Apprasal TA 204 -Denosumab for the prevention of osteoporotic fractures in postmenopausal women. October Scottish Intercollegiate Guidelines Network (SIGN) Guideline 71.Management of Osteoporosis Annex 4 - Calculate your Calcium. ( ork Prepared by: Kathleen Hayes, Pharmacist, Medicines Management Team, Solent NHS Trust, in collaboration with Prof. C Cooper, Professor of Rheumatology, University of Southampton School of Medicine, Dr Gill Pearson, Associate Specialist in Rheumatology, Southampton, Dr Annie Cooper, Consultant Rheumatologist, Winchester, Dr Peter Prouse, Consultant Rheumatologist, Basingstoke. Basingstoke Southampton and Winchester District Prescribing Committee Approved by: Date: June 2013 Renewal date June of 10 pages

10 Appendix 1 Management of bone loss in early breast cancer 10 of 10 pages Reid DM, Doughty J, Eastell R, Heys SD, Howell A, McCloskey EV, Powles T, Selby P, Coleman RE. Guidance for the management of breast cancer treatmentinduced bone loss: a consensus position statement from a UK Expert Group Cancer Treat Rev 2008;34:S1 S18.